Therapeutic ureas

ABSTRACT

This invention relates to urea compounds that are muscarinic receptor antagonists and agonists, pharmaceutical compositions comprising such compounds, and methods of preparing these compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 09/456,170, now abandoned filed Dec. 7, 1999.

BACKGROUND OF THE INVENTION

A receptor is a biological structure with one or more binding domainsthat reversibly complexes with one or more ligands, where thatcomplexation has biological consequences. Receptors can exist entirelyoutside the cell (extracellular receptors), within the cell membrane(but presenting sections of the receptor to the extracellular milieu andcytosol), or entirely within the cell (intracellular receptors). Theymay also function independently of a cell (e.g., clot formation).Receptors within the cell membrane allow a cell to communicate with thespace outside of its boundaries (i.e., signaling) as well as to functionin the transport of molecules and ions into and out of the cell.

A ligand is a binding partner for a specific receptor or family ofreceptors. A ligand may be the endogenous ligand for the receptor oralternatively may be a synthetic ligand for the receptor such as a drug,a drug candidate or a pharmacological tool.

The super family of seven transmembrane proteins (7-TMs), also calledG-protein coupled receptors (GPCRs), represents one of the mostsignificant classes of membrane bound receptors that communicate changesthat occur outside of the cell's boundaries to its interior, triggeringa cellular response when appropriate. The G-proteins, when activated,affect a wide range of downstream effector systems both positively andnegatively (e.g., ion channels, protein kinase cascades, transcription,transmigration of adhesion proteins, and the like).

Muscarinic receptors are members of the G-protein coupled receptors thatare composed of a family of five receptor sub-types (M₁, M₂, M₃, M₄ andM₅) and are activated by the neurotransmitter acetylcholine. Thesereceptors are widely distributed on multiple organs and tissues and arecritical to the maintenance of central and peripheral cholinergicneurotransmission. The regional distribution of these receptor subtypesin the brain and other organs has been documented (Bonner, T. I. et al.,Science (Washington D.C.) 1987, 237, 527-532; Goyal, R. K., J. Med.,1989, 321, 1022; Hulme, E. C., et al., Annu. Rev. harmacol. Toxicol.1990, 30, 633; and Eglen, R. M. and Hegde, S. S., Drug News Perspect.1997, 10(8), 462-469). For example, the smooth muscle is composedlargely of M₂ and M₃ receptors, cardiac muscle is composed largely of M₂receptors, and salivary glands are largely composed of M₃ receptors.

It has been established that the muscarinic receptors are involved indiseases such as chronic obstructive pulmonary disease, asthma,irritable bowel syndrome, urinary incontinence, rhinitis, spasmodiccolitis, chronic cystitis, and alzheimer,s disease, senile dementia,glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiacarrhythmia, and hyper salvation syndromes (Fisher, A., Invest. Drugs,1997, 6(10), 1395-1411; Martel, A. M., et al., Drugs Future, 1997,22(2), 135-137; Graul, A. and Castaner, J., Drugs Future, 1996, 21(11),1105-1108; and Graul, A., et al., Drugs Future, 1997, 22(7), 733-737).

A number of compounds having muscarinic receptor antagonistic activitiesare being used to treat these diseases. For example, oxybutynin is beingused for the treatment of urinary urge incontinence and dicyclorine isbeing used for the treatment of irritable bowel syndrome. However, thesedrugs have limited utility as they produce side effects such as drymouth, blurred vision, and mydriasis.

There is currently a need for novel muscarinic receptor antagonists.

SUMMARY OF THE INVENTION

The invention is directed to urea derivatives that are muscarinicreceptor antagonists and agonists and that are useful in the treatmentand prevention of diseases mediated by muscarinic receptors (e.g.chronic obstructive pulmonary disease, chronic bronchitis, irritablebowel syndrome, urinary incontinence, and the like).

Accordingly, the invention provides a compound of the invention which isa compound of Formula (I):

L₁—X—L₂

wherein:

wherein:

A is an aryl or a heteroaryl ring;

B″ is —NR^(a−) wherein R^(a) is hydrogen, alkyl, aryl, heteroaryl, orsubstituted alkyl;

R¹ is hydrogen or alkyl;

R² is Het, or is selected from a group consisting of formula (i), (ii),and (iii):

wherein:

—— is an optional double bond;

n₁ is an integer of from 1 to 4;

n₂ is an integer of from 1 to 3;

V is —CH—, —O—, —S(O)n₃— (where n₃ is an integer of from 0 to 2), or—NR⁴— (wherein R⁴ is hydrogen, alkyl, substituted alkyl, aryl, orheteroaryl);

“Het” is a heteroaryl ring which optionally attaches (a) to a linker;

R³ is hydrogen, alkyl, amino, substituted amino, —OR^(a) (where R^(a) ishydrogen, alkyl, or acyl), or a covalent bond attaching (a) to a linker;

R⁵ is hydrogen, alkyl, amino, substituted amino, —OR^(b) (where R^(b) ishydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bondattaching (a) to a linker;

R⁶, R⁷, and R⁸ are, independently of each other, hydrogen, halo,hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionallysubstituted with one, two or three substituents selected from halo,hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino,substituted amino, or a covalent bond attaching (a) to a linker;

K is a bond or an alkylene group;

K″ is a bond, —C(O)—, —S(O)_(n4)— (where n₄ is an integer of from 0 to2), or an alkylene group optionally substituted with a hydroxyl group;and

B is heterocycloamino or heteroarylamino, which optionally attaches (a)to a linker;

provided that at least one of the R⁵, R⁶, R⁷, R⁸, “Het”,heterocycloamino or heteroarylamino groups attaches (a) to a linker;

X is a linker;

L₂ is a group selected from a group consisting of:

(i) a group of formula (b):

wherein:

D″ is alkylene;

D is —NR³¹R³², —N⁺(R³³R³⁴R³⁵) or —OR³² where R³¹, R³³, and R³⁴ are,independently of each other, hydrogen, alkyl, or aralkyl; and R³² andR³⁵ represent a covalent bond attaching (b) to a linker;

R²⁷ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy,alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl,sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono ordialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio,heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy,aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two orthree substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl,alkylthio, alkylsulfonyl, amino, or substituted amino;

R²⁸ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy,alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl,sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono ordialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionallysubstituted with one, two, or three substituents selected from halo,hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, orsubstituted amino;

R²⁹ and R³⁰ are, independently of each other, hydrogen, alkyl,haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl,thio, alkylthio, amino, mono- or dialkylamino; or

one of R²⁷, R²⁸, R²⁹, or R³⁰ together with the adjacent group forms amethylenedioxy or ethylenedioxy group;

(ii) a group of formula (c):

wherein:

n₁₁ is an integer of from 1 to 7;

n₁₂ is 0 to 7;

F is —NR⁴⁰—, —O—, —S—, or —CHR⁴¹— (wherein R⁴⁰ and R⁴¹ are,independently of each other, hydrogen, alkyl, or substituted alkyl);

F″ is a covalent bond, —OR⁴³, —NR⁴²R⁴³, or —N⁺R⁴³R⁴⁴R⁴⁵ wherein R⁴² ishydrogen or alkyl, R⁴⁴ and R⁴⁵ are alkyl, and R⁴³ is hydrogen, alkyl, ora covalent bond attaching (c) to a linker;

R³⁶ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy,alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl,sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono ordialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio,heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy,aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two orthree substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl,alkylthio, alkylsulfonyl, amino, or substituted amino;

R³⁷ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy,alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino,aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio,heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyloptionally substituted with one, two or three substituents selected fromhalo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino,or substituted amino; and

R³⁸ is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bondattaching the ligand to a linker provided that at least one of R³⁸ andR⁴³ attaches (c) to a linker;

R³⁹ is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl; and

(iii) a group of formula (d) or (e):

wherein:

R⁴⁶ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, orheterocycle;

R⁴⁷ is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR⁵⁰where R⁵⁰ is alkyl; or

R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attachedform heterocycle, which heterocycle, in addition to optionally bearingthe optional substituents defined hereinbelow for a heterocycle, canalso optionally be substituted with one or more (e.g. 1, 2, 3, or 4)alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, orsubstituted alkynyl.

R⁴⁸ is a covalent bond that attaches the (d) or the (e) to a linker; and

R⁴⁹ is alkyl;

or a pharmaceutically acceptable salt; or prodrug thereof.

Preferably X is a group of formula:

—X^(a)—Z—(Y^(a)—Z)_(m)—Y^(b)—Z—X^(a)—

wherein

m is an integer of from 0 to 20;

X^(a) at each separate occurrence is selected from the group consistingof —O—, —S—,—NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR—or a covalent bond where R is as defined below;

Z at each separate occurrence is selected from the group consisting ofalkylene, substituted alkylene, cycloalkylene, substitutedcylcoalkylene, alkenylene, substituted alkenylene, alkynylene,substituted alkynylene, cycloalkenylene, substituted cycloalkenylene,arylene, heteroarylene, heterocyclene, or a covalent bond;

Y^(a) and Y^(b) at each separate occurrence are selected from the groupconsisting of —O—, —C(O)—, —OC(O)—, —C(O)O—,—NR—, —S(O)n—, —C(O)NR′—,—NR′C(O)—, —NR′C(O)NR′—, —NR′C(S)NR′—, —C(—NR′)—NR′—, —NR′—C(—NR′)—,—OC(O)—NR′—, —NR′—C(O)—O—, —N—C(R″)—NR′—, —NR′—C(R″)—N—,—P(O)(OR′)—O—,—O—P(O)(OR′), S(O)_(n)CR′R″—, —S(O)_(n)—, —NR′—, —NR′—S(O)_(n)—,—S—S—,and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at eachseparate occurrence are selected from the group consisting of hydrogen,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl,substituted alkynyl, aryl, heteroaryl and heterocyclic (preferably, atleast one of X^(a), Y^(a), Y^(b) or Z is not a covalent bond).

The invention also provides a compound of the invention which is acompound of formula (IV):

wherein R², K″, A, K, R¹, B″, B, X, and L₂ have any of the valuesdefined herein; or a pharmaceutically acceptable salt; or prodrugthereof. A preferred compound of the invention is a compound of formula(IVa):

wherein X, and L₂ have any of the values defined herein; or apharmaceutically acceptable salt; or prodrug thereof.

The invention also provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of the invention or apharmaceutically acceptable salt or prodrug thereof.

The invention also provides synthetic intermediates disclosed herein, aswell as synthetic methods useful for preparing such intermediates, andsynthetic methods useful for preparing compounds of the invention orsalts thereof.

The invention also provides a method of treating diseases mediated by amuscarinic receptor in a mammal, comprising administering to said mammala therapeutically effective amount of a compound of the invention or apharmaceutically acceptable salt or prodrug thereof.

The invention also provides a compound of the invention or apharmaceutically acceptable salt or prodrug thereof for use in medicaltherapy, as well as the use of a compound of Formula (I) or apharmaceutically acceptable salt or prodrug thereof in the preparationof a medicament for the treatment of a disease mediated by a muscarinicreceptor in a mammal.

Applicant has discovered that urea compounds of the present inventionare metabolically more stable than compounds lacking such a ureafunctionality. Accordingly, compounds of the present invention havelonger metabolic half-lives and/or longer duration of action in vivo,which can reduce the dose required for administration or can reduce thelikelihood of the generation of unwanted metabolites.

DETAILED DESCRIPTION OF THE INVENTION

The following terms have the following meanings unless otherwiseindicated. Any undefined terms have their art recognized meanings.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain preferably having from 1 to 40 carbon atoms,more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6carbon atoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl,and the like.

The term “substituted alkyl” refers to an alkyl group as defined abovewherein one or more carbon atoms in the alkyl chain have been optionallyreplaced with a heteroatom such as —O—, —S(O)n— (where n is 0 to 2),—NR— (where R is hydrogen or alkyl) and having from 1 to 5 substituentsselected from the group consisting of alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-aryl,—SO₂-heteroaryl, and —NR^(a)R^(b), wherein R^(a) and R^(b) may be thesame or different and and are chosen from hydrogen, optionallysubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,heteroaryl and heterocyclic. This term is exemplified by groups such ashydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl,2-methylaminoethyl, 3-dimethylaminopropyl, 2-sulfonamidoethyl,2-carboxyethyl, and the like.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, preferably having from 1 to 40 carbonatoms, more preferably 1 to 10 carbon atoms and even more preferably 1to 6 carbon atoms. This term is exemplified by groups such as methylene(—CH₂—), ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂—and —CH(CH₃)CH₂—) and the like.

The term “substituted alkylene” refers to an alkylene group, as definedabove, having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl. Additionally, such substituted alkylene groupsinclude those where 2 substituents on the alkylene group are fused toform one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fusedto the alkylene group. Preferably such fused groups contain from 1 to 3fused ring structures.

The term “alkylaminoalkyl”, “alkylaminoalkenyl” and “alkylaminoalkynyl”refers to the groups R^(a)NHR^(b)— where R^(a) is alkyl group as definedabove and R^(b) is alkylene, alkenylene or alkynylene group as definedabove. Such groups are exemplified by 3-methylaminobutyl,4-ethylamino-1,1-dimethylbutyn-1-yl, 4-ethylaminobutyn-1-yl, and thelike.

The term “alkaryl” or “aralkyl” refers to the groups -alkylene-aryl and-substituted alkylene-aryl where alkylene, substituted alkylene and arylare defined herein. Such alkaryl groups are exemplified by benzyl,phenethyl and the like.

The term “alkoxy” refers to the groups alkyl-O—, alkenyl-O—,cycloalkyl-O—, cycloalkenyl-O—, and alkynyl-O—, where alkyl, alkenyl,cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferredalkoxy groups are alkyl-O— and include, by way of example, methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

The term “substituted alkoxy” refers to the groups substituted alkyl-O—,substituted alkenyl-O—, substituted cycloalkyl-O—, substitutedcycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl,substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyland substituted alkynyl are as defined herein.

The term “haloalkoxy” refers to the groups alkyl-O— wherein one or morehydrogen atoms on the alkyl group have been substituted with a halogroup and include, by way of examples, groups such as trifluoromethoxy,and the like.

The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl,alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, andsubstituted alkylene-substituted alkyl wherein alkyl, substituted alkyl,alkylene and substituted alkylene are as defined herein. Preferredalkylalkoxy groups are alkylene-O-alkyl and include, by way of example,methylenemethoxy (—CH₂OCH₃), ethylenemethoxy (—CH₂CH₂OCH₃),n-propylene-iso-propoxy (—CH₂CH₂CH₂OCH(CH₃)₂), methylene-t-butoxy(—CH₂—O—C(CH₃)₃), and the like.

The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl,alkylene-S-substituted alkyl, substituted alkylene-S-alkyl andsubstituted alkylene-S-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, byway of example, methylenethiomethoxy (—CH₂SCH₃), ethylenethiomethoxy(—CH₂CH₂SCH₃), n-propylene-iso-thiopropoxy (—CH₂CH₂CH₂SCH(CH₃)₂),methylene-t-thiobutoxy (—CH₂SC(CH₃)₃), and the like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2 to 40 carbonatoms, more preferably 2 to 10 carbon atoms and even more preferably 2to 6 carbon atoms and having at least 1 and preferably from 1-6 sites ofvinyl unsaturation. Preferred alkenyl groups include ethenyl (—CH═CH₂),n-propenyl (—CH₂CH═CH₂), iso-propenyl (—C(CH₃)═CH₂), and the like.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “alkenylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2 to 40 carbonatoms, more preferably 2 to 10 carbon atoms and even more preferably 2to 6 carbon atoms and having at least 1 and preferably from 1-6 sites ofvinyl unsaturation. This term is exemplified by groups such asethenylene (—CH═CH—), the propenylene isomers (e.g., —CH₂CH═CH— or—C(CH₃)═CH—), and the like.

The term “substituted alkenylene” refers to an alkenylene group asdefined above having from 1 to 5 substituents, and preferably from 1 to3 substituents, selected from the group consisting of alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substitutedamino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen,hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl. Additionally,such substituted alkenylene groups include those where 2 substituents onthe alkenylene group are fused to form one or more cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,heterocyclic or heteroaryl groups fused to the alkenylene group.

The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbonpreferably having from 2 to 40 carbon atoms, more preferably 2 to 20carbon atoms and even more preferably 2 to 6 carbon atoms and having atleast 1 and preferably from 1-6 sites of acetylene (triple bond)unsaturation. Preferred alkynyl groups include ethynyl (—C≡CH),propargyl (—CH₂C≡CH), and the like.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl,and —SO₂-heteroaryl.

The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon preferably having from 2 to 40 carbon atoms, more preferably2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms andhaving at least 1 and preferably from 1-6 sites of acetylene (triplebond) unsaturation. Preferred alkynylene groups include ethynylene(—C≡C—), propargylene (—CH₂C≡C—), and the like.

The term “substituted alkynylene” refers to an alkynylene group asdefined above having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “acyl” refers to the groups HC(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—,heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl, and heterocyclic are as defined herein.

The term “acylamino” or “aminocarbonyl” refers to the group —C(O)NRRwhere each R is independently hydrogen, alkyl, substituted alkyl, aryl,heteroaryl, heterocyclic or where both R groups are joined to form aheterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl,aryl, heteroaryl, and heterocyclic are as defined herein.

The term “aminoacyl” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, orheterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl, andheterocyclic are as defined herein.

The term “aminoacyloxy” or “alkoxycarbonylamino” refers to the group—NRC(O)OR where each R is independently hydrogen, alkyl, substitutedalkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substitutedalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

The term “acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclic-C(O)O— wherein alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,and heterocyclic are as defined herein.

The term “aryl” refers to an unsaturated aromatic carbocyclic group offrom 6 to 20 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferredaryls include phenyl, naphthyl and the like. Unless otherwiseconstrained by the definition for the aryl substituent, such aryl groupscan optionally be substituted with from 1 to 5 substituents, preferably1 to 3 substituents, selected from the group consisting of acyloxy,hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, substituted alkyl, substituted alkoxy, substitutedalkenyl, substituted alkynyl, substituted cycloalkyl, substitutedcycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl,aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro,heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy,oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioheteroaryloxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl,—SO₂-heteroaryl and trihalomethyl. Preferred aryl substituents includealkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above including optionally substituted aryl groups as alsodefined above.

The term “arylene” refers to the diradical derived from aryl (includingsubstituted aryl) as defined above and is exemplified by 1,2-phenylene,1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl,substituted alkynyl, aryl, heteroaryl, and heterocyclic provided thatboth R's are not hydrogen.

The term “carboxyalkyl” or “alkoxycarbonyl” refers to the groups“—C(O)O-alkyl”, “—C(O)O-substituted alkyl”, “—C(O)O-cycloalkyl”,“—C(O)O-substituted cycloalkyl”, “—C(O)O-alkenyl”, “—C(O)O-substitutedalkenyl”, “—C(O)O-alkynyl” and “—C(O)O-substituted alkynyl” where alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl and substituted alkynyl alkynyl are asdefined herein.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups havingfrom 1 to 5 substituents, and preferably 1 to 3 substituents, selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

The term “cycloalkenyl” refers to cyclic alkenyl groups of from 4 to 20carbon atoms having a single cyclic ring and at least one point ofinternal unsaturation. Examples of suitable cycloalkenyl groups include,for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl, andthe like.

The term “substituted cycloalkenyl” refers to cycloalkenyl groups havingfrom 1 to 5 substituents, and preferably 1 to 3 substituents, selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

The term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

The term “heteroaryl” refers to an aromatic group of from 1 to 15 carbonatoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfurwithin at least one ring (if there is more than one ring). Unlessotherwise constrained by the definition for the heteroaryl substituent,such heteroaryl groups can be optionally substituted with 1 to 5substituents, preferably 1 to 3 substituents, selected from the groupconsisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkoxy, substituted alkenyl, substituted alkynyl, substitutedcycloalkyl, substituted cycloalkenyl, amino, substituted amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro,trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a singlering (e.g., pyridyl or furyl) or multiple condensed rings (e.g.,indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl,pyrrolyl and furyl.

The term “heteroaralkyl” refers to the groups -alkylene-heteroaryl wherealkylene and heteroaryl are defined herein. Such heteroaralkyl groupsare exemplified by pyridylmethyl, pyridylethyl, indolylmethyl, and thelike.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “heteroarylene” refers to the diradical group derived fromheteroaryl (including substituted heteroaryl), as defined above, and isexemplified by the groups 2,6-pyridylene, 2,4-pyridiylene,1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene,2,5-pyridnylene, 2,5-indolenyl, and the like.

The term “heterocycle” or “heterocyclic” or refers to a monoradicalsaturated unsaturated group having a single ring or multiple condensedrings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring. Unless otherwise constrainedby the definition for the heterocyclic substituent, such heterocyclicgroups can be optionally substituted with 1 to 5, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl. Such heterocyclic groups can have a single ring ormultiple condensed rings. Preferred heterocyclics include morpholino,piperidinyl, and the like.

Examples of nitrogen heteroaryls and heterocycles include, but are notlimited to, pyrrole, thiophene, furan, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, pyrrolidine, piperidine, piperazine,indoline, morpholine, tetrahydrofuranyl, tetrahydrothiophene, and thelike as well as N-alkoxy-nitrogen containing heterocycles.

The term “heterocyclooxy” refers to the group heterocyclic-O—.

The term “thioheterocyclooxy” refers to the group heterocyclic-S—.

The term “heterocyclene” refers to the diradical group formed from aheterocycle, as defined herein, and is exemplified by the groups2,6-morpholino, 2,5-morpholino and the like.

“Heteroarylamino” means a 5 membered aromatic ring wherein one or tworing atoms are N, the remaining ring atoms being C. The heterocycloaminoring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it maybe optionally substituted with one or more substituents, preferably oneor two substituents, selected from alkyl, substituted alkyl, cycloalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino,substituted amino, acylamino, —OR (where R is hydrogen, alkyl, alkenyl,cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or—S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (providedthat n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl,heteroaryl, aralkyl, or heteroaralkyl]. More specifically the termheterocycloamino includes, but is not limited to, imidazole, pyrazole,benzimidazole and benzpyrazole.

“Heterocycloamino” means a saturated monovalent cyclic group of 4 to 8ring atoms, wherein at least one ring atom is N and optionally containsone or two additional ring heteroatoms selected from the groupconsisting of N, O, or S(O)n (where n is an integer from 0 to 2), theremaining ring atoms being C, where one or two C atoms may optionally bereplaced by a carbonyl group. The heterocycloamino ring may be fused toa cycloalkyl, aryl or heteroaryl ring, and it may be optionallysubstituted with one or more substituents, preferably one or twosubstituents, selected from alkyl, substituted alkyl, cycloalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino,substituted amino, acylamino, —OR (where R is hydrogen, alkyl, alkenyl,cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or—S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (providedthat n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl,heteroaryl, aralkyl, or heteroaralkyl]. More specifically the termheterocycloamino includes, but is not limited to, pyrrolidino,piperidino, morpholino, piperazino, indolino, or thiomorpholino. Theterm heterocycloamino also includes, quinuclidine,1-azabicyclo[2.2.1]heptyl, 1-azabicyclo[3.2.1]octyl and the derivativesthereof.

The term “oxyacylamino” or “aminocarbonyloxy” refers to the group—OC(O)NRR where each R is independently hydrogen, alkyl, substitutedalkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substitutedalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “spiro-attached cycloalkyl group” refers to a cycloalkyl groupattached to another ring via one carbon atom common to both rings.

The term “thiol” refers to the group —SH.

The term “thioalkoxy” or “alkylthio” refers to the group —S-alkyl.

The term “substituted thioalkoxy” refers to the group —S-substitutedalkyl.

The term “thioaryloxy” refers to the group aryl-S— wherein the arylgroup is as defined above including optionally substituted aryl groupsalso defined above.

The term “thioheteroaryloxy” refers to the group heteroaryl-S— whereinthe heteroaryl group is as defined above including optionallysubstituted aryl groups as also defined above.

As to any of the above groups which contain one or more substituents, itis understood, of course, that such groups do not contain anysubstitution or substitution patterns which are sterically impracticaland/or synthetically non-feasible. In addition, the compounds of thisinvention include all stereochemical isomers arising from thesubstitution of these compounds.

Unless specified otherwise, all ranges referred to herein include thestated end-point values.

The term “pharmaceutically-acceptable salt” refers to salts which retainbiological effectiveness and are not biologically or otherwiseundesirable. In many cases, the compounds of this invention are capableof forming acid and/or base salts by virtue of the presence of aminoand/or carboxyl groups or groups similar thereto.

Pharmaceutically-acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases, includeby way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group. Examples of suitable amines include, by way of exampleonly, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-alkylglucamines, theobromine, purines, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like. It should also beunderstood that other carboxylic acid derivatives would be useful in thepractice of this invention, for example, carboxylic acid amides,including carboxamides, lower alkyl carboxamides, dialkyl carboxamides,and the like.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

The term “pharmaceutically-acceptable cation” refers to the cation of apharmaceutically-acceptable salt.

The term “protecting group” or “blocking group” refers to any groupwhich when bound to one or more hydroxyl, thiol, amino or carboxylgroups of the compounds (including intermediates thereof) preventsreactions from occurring at these groups and which protecting group canbe removed by conventional chemical or enzymatic steps to reestablishthe hydroxyl, thiol, amino or carboxyl group. The particular removableblocking group employed is not critical and preferred removable hydroxylblocking groups include conventional substituents such as allyl, benzyl,acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl,t-butyl-diphenylsilyl and any other group that can be introducedchemically onto a hydroxyl functionality and later selectively removedeither by chemical or enzymatic methods in mild conditions compatiblewith the nature of the product. Preferred removable thiol blockinggroups include disulfide groups, acyl groups, benzyl groups, and thelike. Preferred removable amino blocking groups include conventionalsubstituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ),fluorenylmethoxy-carbonyl (FMOC), allyloxycarbonyl (ALOC), and the likewhich can be removed by conventional conditions compatible with thenature of the product. Preferred carboxyl protecting groups includeesters such as methyl, ethyl, propyl, t-butyl etc. which can be removedby mild conditions compatible with the nature of the product.

The term “optional” or “optionally” means that the subsequentlydescribed event, circumstance or substituent may or may not occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

The term “inert organic solvent” or “inert organic solvent” means asolvent which is inert under the conditions of the reaction beingdescribed in conjunction therewith including, by way of example only,benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide,chloroform, methylene chloride, diethyl ether, ethyl acetate, acetone,methylethyl ketone, methanol, ethanol, propanol, isopropanol, t-butanol,dioxane, pyridine, and the like. Unless specified to the contrary, thesolvents used in the reactions described herein are inert solvents.

The term “treatment” refers to any treatment of a pathologic conditionin a mammal, particularly a human, and includes:

(i) preventing the pathologic condition from occurring in a subjectwhich may be predisposed to the condition but has not yet been diagnosedwith the condition and, accordingly, the treatment constitutesprophylactic treatment for the disease condition;

(ii) inhibiting the pathologic condition, i.e., arresting itsdevelopment;

(iii) relieving the pathologic condition, i.e., causing regression ofthe pathologic condition; or

(iv) relieving the conditions mediated by the pathologic condition.

The term “pathologic condition which is modulated by treatment with aligand” covers all disease states (i.e., pathologic conditions) whichare generally acknowledged in the art to be usefully treated with aligand for the muscarinic receptors in general, and those disease stateswhich have been found to be usefully treated by a compound of theinvention. Such disease states include, by way of example only, thetreatment of a mammal afflicted with chronic obstructive pulmonarydisease, chronic bronchitis, irritable bowel syndrome, urinaryincontinence, and the like.

The term “therapeutically effective amount” refers to that amount of acompound which is sufficient to effect treatment, as defined above, whenadministered to a mammal in need of such treatment. The therapeuticallyeffective amount will vary depending upon the subject and diseasecondition being treated, the weight and age of the subject, the severityof the disease condition, the manner of administration and the like,which can readily be determined by one of ordinary skill in the art.

The term “linker”, identified by the symbol ‘X’ refers to a group orgroups that covalently attaches L₁ and L₂. Additionally, the linker canbe either a chiral or achiral molecule. The term “linker” does not,however, extend to cover solid inert supports such as beads, glassparticles, fibers, and the like. But it is understood that the compoundsof this invention can be attached to a solid support if desired. Forexample, such attachment to solid supports can be made for use inseparation and purification processes and similar applications.

“Pro-drugs” means any compound which releases an active parent drugaccording to Formula (I) in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of Formula (I) are prepared bymodifying functional groups present in the compound of Formula (I) insuch a way that the modifications may be cleaved in vivo to release theparent compound. Prodrugs include compounds of Formula (I) wherein ahydroxy, amino, or sulfhydryl group in compound (I) is bonded to anygroup that may be cleaved in vivo to regenerate the free hydroxyl,amino, or sulfhydryl group, respectively. Examples of prodrugs include,but are not limited to esters (e.g., acetate, formate, and benzoatederivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyfunctional groups in compounds of Formula (I), and the like.

While the broadest definition of this invention is set forth in theSummary of the Invention, certain compounds of Formula (I) may bepreferred. Specific and preferred values listed herein for radicals,substituents, and ranges, are for illustration only; they do not excludeother defined values or other values within defined ranges for theradicals and substituents

A preferred value for A is phenyl or pyridine

A preferred value for R¹ is hydrogen methyl, or ethyl.

Another preferred value for R¹ is hydrogen.

A preferred value for R² is pyrrolyl, pyridinyl, or imidazolyl.

Another preferred value for R² is phenyl.

A preferred value for V is —CH— or —NR⁴— (wherein R⁴ is hydrogen, alkyl,substituted alkyl, aryl, or heteroaryl).

A preferred value for R³ is hydrogen or alkyl

A preferred value for R⁵ is hydrogen, alkyl, aryl, aralkyl,heteroaralkyl, or a covalent bond attaching (a) to a linker

Another preferred value for R⁵ is hydrogen, methyl, phenyl optionallysubstituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino, benzyloptionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, oramino.

A preferred value for R⁶, R⁷, and R⁸ independent of each other ishydrogen, alkyl, nitro, hydroxy, or amino.

A preferred value for K is alkylene having from 1 to 10 carbon atoms.

A preferred value for K is alkylene having from 1 to 5 carbon atoms.

A preferred value for K is a bond or a methylene group.

A preferred value for K″ is a bond.

A preferred value for R_(a) is hydrogen.

A preferred value for B is a heterocycloamino group which attaches (a)to a linker.

Another preferred value for B is a formula selected from a groupconsisting of formula (j), formula (k), and formula (l):

wherein:

n₁₃ and n₁₄ are, independently of each other, an integer of from 0 to 4provided that n₁₃+n₁₄ is an integer of from 3 to 5;

n₁₅ and n₁₇ are, independently of each other, an integer of from 0 to 4provided that n₁₅+n₁₇ is an integer of from 3 to 5;

n₁₆ is an integer of from 0 to 3 provided that n₁₅+n₁₆ is an integer offrom 3 to 5;

n₁₈, n₁₉ and n₂₀ are, independently of each other, an integer of from 0to 3 provided that n₁₈+n₁₉+n₂₀ is 2 or 3;

n₂₁ is an integer of from 1 to 3;

W^(a) and W^(c) are, independently of each other:

where:

n₂₂ is 0 or 1;

R⁵³ and R⁵⁴ are, independently of each other, hydrogen, alkyl, alkenyl,alkynyl, cycloalkylalkyl, aralkyl, or heterocyclylalkyl or a covalentbond attaching (a) to a linker;

R⁵⁵ is alkyl, alkenyl or alkynyl; and

W^(b) is —N(O)n₂₃ or —N⁺—R⁵⁶ where n₂₃ is 0 or 1, and R⁵⁶ is alkyl,alkenyl, alkynyl, or aralkyl, or a covalent bond attaching (a) to alinker;

provided that a carbon other than a bridge head carbon is bonded to B″.

Another preferred value for B is a ring represented by the followinggeneral formulae:

wherein a carbon atom other than a bridge head carbon is bound to B″;and W^(c) is as defined above.

A more preferred value for B is pyrrolidine, piperidine, orhexahydroazepine attaching (a) to a linker.

Another more preferred value for B is piperidine wherein the nitrogenatom of said piperidine attaches (a) to a linker.

Another more preferred value for B is piperidin-4-yl wherein thenitrogen at the 1 position optionally attaches (a) to a linker.

Another more preferred value for B is quinuclidine,1-azabicyclo[2.2.1]-heptyl, or 1-azabicyclo[3.2.1]octyl attaching (a) toa linker, wherein a carbon other than a bridge head carbon is bound toB″.

A preferred value for D″ is —(CH₂)n₄₃— where n₄₃ is an integer of from1-10, preferably 2-8, more preferably 2-4. Another preferred value forn₄₃ is an integer of from 3-10.

A preferred value for D is —NR³¹R³² or —N⁺(R³³R³⁴R³⁵)M⁻ where R³¹, R³³,and R³⁴ are, independently of each other, hydrogen or methyl, and R³²and R³⁵ represent a covalent bond attaching (b) to a linker. Morepreferably R³¹, R³³, and R³⁴ methyl, and R³² and R³⁵ represent acovalent bond attaching (b) to a linker.

A preferred value for R²⁷ is hydrogen.

A preferred value for R²⁸ is hydrogen.

A preferred value for R²⁹ and R³⁰ independently is hydrogen; or one ofR²⁷, R²⁸, R²⁹, or R³⁰ together with the adjacent group forms amethylenedioxy or ethylenedioxy group.

A preferred value for n₁₁ is 1.

A preferred value for n₁₂ is 6.

A preferred value for F is —O—.

A preferred value for F″ is a covalent bond, —OR⁴³, —NR⁴²R⁴³ wherein R⁴²is hydrogen or alkyl, or —N⁺(R⁴³R⁴⁴R⁴⁵) wherein R⁴⁴ and R⁴⁵ are alkyl,and R⁴³ is a covalent bond attaching (c) to a linker.

A preferred value for F″ is —O—, —NH—, N(CH₃)— or —N(CH₃)₂—

A more preferred value for F″ is —NH—, N(CH₃)— or —N(CH₃)₂— wherein thenitrogen atom attaches (c) to a linker.

A preferred value for R³⁶ is hydrogen.

Preferably R³⁷ is ortho to the —(CHR³⁸)— group and is hydrogen oralkoxy. More preferably R³⁷ is ortho to the —(CHR³⁸) group and ismethoxy.

Preferably is R³ is hydrogen.

Preferably R³⁹ is hydrogen.

Preferably L₂ is a group of formula (d) wherein: R⁴⁶ is alkyl orsubstituted alkyl; R⁴⁷ is alkyl, substituted alkyl, or heterocycle; orR⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attachedform heterocycle.

Preferably, L₂ is a group of formula A1-A241 as shown in the followingtable. L₂ is preferably linked to X through a non-aromatic nitrogen atom(e.g. a secondary amino nitrogen) of L₂.

No. L₂ A1 

A2 

A3 

A4 

A5 

A6 

A7 

A8 

A9 

A10 

A11 

A12 

A13 

A14 

A15 

A16 

A17 

A18 

A19 

A20 

A21 

A22 

A23 

A24 

A25 

A26 

A27 

A28 

A29 

A30 

A31 

A32 

A33 

A34 

A35 

A36 

A37 

A38 

A39 

A40 

A41 

A42 

A43 

A44 

A45 

A46 

A47 

A48 

A49 

A50 

A51 

A52 

A53 

A54 

A55 

A56 

A57 

A58 

A59 

A60 

A61 

A62 

A63 

A64 

A65 

A66 

A67 

A68 

A69 

A70 

A71 

A72 

A73 

A74 

A75 

A76 

A77 

A78 

A79 

A80 

A81 

A82 

A83 

A84 

A85 

A86 

A87 

A88 

A89 

A90 

A91 

A92 

A93 

A94 

A95 

A96 

A97 

A98 

A99 

A100

A101

A102

A103

A104

A105

A106

A107

A108

A109

A110

A111

A112

A113

A114

A115

A116

A117

A118

A119

A120

A121

A122

A123

A124

A125

A126

A127

A128

A129

A130

A131

A132

A133

A134

A135

A136

A137

A138

A139

A140

A141

A142

A143

A144

A145

A146

A147

A148

A149

A150

A151

A152

A153

A154

A155

A156

A157

A158

A159

A160

A161

A162

A163

A164

A165

A166

A167

A168

A169

A170

A171

A172

A173

A174

A175

A176

A177

A178

A179

A180

A181

A182

A183

A184

A185

A186

A187

A188

A189

A190

A191

A192

A193

A194

A195

A196

A197

A198

A199

A200

A201

A202

A203

A204

A205

A206

A207

A208

A209

A210

A211

A212

A213

A214

A215

A216

A217

A218

A219

A220

A221

A222

A223

A224

A225

A226

A227

A228

A229

A230

A231

A232

A233

A234

A235

A236

A237

A238

A239

A240

A241

Preferably, L₂ can also be a group of formula A301-A439 as shown in thefollowing table. L₂ is preferably linked to X through a non-aromaticnitrogen atom (e.g. a secondary amino nitrogen) of L₂.

A301

A302

A303

A304

A305

A306

A307

A308

A309

A310

A311

A312

A313

A314

A315

A316

A317

A318

A319

A320

A321

A322

A323

A324

A325

A326

A327

A328

A329

A330

A331

A332

A333

A334

A335

A336

A337

A338

A339

A340

A341

A342

A343

A344

A345

A346

A347

A348

A349

A350

A351

A352

A353

A354

A355

A356

A357

A358

A359

A360

A361

A362

A363

A364

A365

A366

A367

A368

A369

A370

A371

A372

A373

A374

A375

A376

A377

A378

A379

A380

A381

A382

A383

A384

A385

A386

A387

A388

A389

A390

A391

A393

A394

A395

A396

A397

A398

A399

A400

A401

A402

A403

A404

A405

A406

A407

A408

A409

A410

A411

A412

A413

A414

A415

A416

A417

A418

A419

A420

A421

A422

A423

A424

A425

A426

A427

A428

A429

A430

A431

A432

A433

A434

A435

A436

A437

A438

A439

Preferably, L₂ can also be a group of formula A501-A523 as shown in thefollowing table. L₂ is preferably linked to X through a non-aromaticnitrogen atom of L₂.

No. L₂ A501

A502

A503

A504

A505

A506

A507

A508

A509

A510

A511

A512

A513

A514

A515

A516

A517

A518

A519

A520

A521

A522

A523

A524

A525

A526

A527

A528

A529

A530

A531

A532

A533

A534

A535

A536

A537

A538

A539

A540

A541

A542

A543

A544

A545

A546

A547

A548

A549

A550

A551

A552

A553

A554

A555

A556

A557

A558

A559

A560

A561

A562

A563

A564

A565

A566

A567

A568

A569

A570

A571

A572

A573

A574

A575

A576

A577

A578

A579

A580

A581

A582

A583

A584

A585

A586

A587

A588

A589

A590

A more preferred value for L₂ is A234, A363, A364, A153, A28, A324,A329, A562, A87, or A239.

A preferred value for X is alkylene optionally substituted with one,two, or three hydroxy groups, alkylene wherein one, two or three carbonatoms have been replaced by an oxygen atom,-alkylene-phenylene-alkylene- wherein the phenylene ring is optionallysubstituted with one or two chloro or fluoro groups.

Another preferred value for X is an alkylene group having from 3 to 20carbon atoms; wherein one or more carbon atoms (e.g. 1, 2, 3, or 4) inthe alkylene group is optionally replaced with —O—; and wherein thechain is optionally substituted on carbon with one or more hydroxyl(e.g. 1, 2, 3, or 4).

Another preferred value for X is an alkylene group having from 6 to 15carbons atoms; wherein one or more carbon atoms (e.g. 1, 2, 3, 4) in thealkylene group is optionally replaced with —O—; and wherein the chain isoptionally substituted on carbon with one or more hydroxyl (e.g. 1, 2,3, or 4).

Another preferred value for X is is nonane-1,9-diyl, octane-1,8-diyl,propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.

Another preferred value for X is a group of the following formula:

wherein the phenyl ring is optionally substituted with 1, 2, or 3 fluorogroups.

Another preferred value for X is a group of one of the followingformulae:

A preferred group of compounds of formula (I) are compounds wherein R²is selected from formula (i) and (iii); and wherein K″ is a bond ormethylene.

A preferred group of compounds of formula (I) are compounds wherein R²is formula (i); R³ is hydrogen, methyl, ethyl, propyl, isopropyl,fluoro, or trifluoromethyl; and K″ is a bond or methylene.

A preferred group of compounds of formula (I) are compounds wherein R²is formula (iii); R⁶, R⁷, and R⁸ are each hydrogen, methyl, ethyl,propyl, isopropyl, fluoro, or trifluoromethyl; and K″ is a bond ormethylene.

A preferred group of compounds are compounds of formula (I) wherein R⁴⁶is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, orheterocycle; R⁴⁷ is alkyl, substituted alkyl, aryl, acyl, heterocycle,or —COOR⁵⁰ where R⁵⁰ is alkyl; or R⁴⁶ and R⁴⁷ together with the nitrogenatom to which they are attached form heterocycle.

A preferred group of compounds are compounds of formula (I) wherein L₂is a group of formula (d) wherein R⁴⁶ and R⁴⁷ together with the nitrogenatom to which they are attached form heterocycle which is substitutedwith 1 to 5 substituents independently selected from the groupconsisting of alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl —SO₂-heteroaryl, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, andsubstituted alkynyl.

A more preferred group of compounds are compounds of formula (I) whereinL₂ is a group of formula (d) wherein R⁴⁶ and R⁴⁷ together with thenitrogen atom to which they are attached form heterocycle which issubstituted with 1 to 3 substituents independently selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, hydroxyamino, alkoxyamino, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.

A preferred group of compounds are compounds of formula (I) wherein L₂is a group of formula (d) wherein R⁴⁶ and R⁴⁷ together with the nitrogenatom to which they are attached form heterocycle which is substitutedwith 1 to 5 substituents independently selected from the groupconsisting of substituted alkyl, alkenyl, substituted alkenyl, alkynyl,and substituted alkynyl.

A preferred group of compounds are compounds of formula (I) wherein L₂is a group of formula (d) wherein at least one of R⁴⁶ and R⁴⁷individually, or R⁴⁶ and R⁴⁷ taken together, is a group that comprises abasic nitrogen atom (e.g. a nitrogen atom with a pKa of preferably atleast about 5, more preferably al least about 6, or most preferably atleast about 7).

A preferred group of compounds are compounds of formula (I) wherein L₂is a group of formula (d) wherein R⁴⁶ is a heterocycle, optionallysubstituted with 1 to 5 substituents independently selected from thegroup consisting of alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, and substituted alkynyl; and R⁴⁷ is alkyl, substitutedalkyl, acyl, or —COOR⁵⁰.

A preferred group of compounds are compounds of formula (1) wherein L₂is a group of formula (d) wherein R⁴⁶ is alkyl that is substituted by agroup that comprises a basic nitrogen atom (e.g. a nitrogen atom with apKa of preferably at least about 5, more preferably al least about 6, ormost preferably at least about 7).

A preferred group of compounds are compounds of formula (I) wherein L₂is a group of formula (d) wherein R⁴⁶ is alkyl that is optionallysubstituted with from 1 to 5 substituents independently selected fromthe group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano,halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,NR^(a)R^(b), wherein R^(a) and R^(b) may be the same or different andand are chosen from hydrogen, alkyl, substituted alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, and heterocyclic.

A preferred group of compounds are compounds of formula (I) wherein L₂is a group of formula (d) wherein R⁴⁶ is a heterocycle which isoptionally substituted with 1 to 5 substituents independently selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl —SO₂-heteroaryl, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, andsubstituted alkynyl.

A preferred group of compounds are compounds of formula (I) wherein L₂is a group of formula (d) wherein R⁴⁶ is 3-piperidinyl, 4-piperidinyl,or 3-pyrrolidinyl, which R⁴⁶ is optionally substituted with 1 to 3substituents independently selected from the group consisting of alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substitutedamino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl,keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, andsubstituted alkynyl.

A preferred group of compounds are compounds of formula (I) wherein R⁴⁶and R⁴⁷ together with the nitrogen atom to which they are attached forma piperidine or pyrrolidine ring which ring is optionally substitutedwith 1 to 3 substituents independently selected from the groupconsisting of alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl,thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy,substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino,alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, and substituted alkynyl.

A preferred group of compounds are compounds of formula (I) wherein R⁴⁶and R⁴⁷ together with the nitrogen atom to which they are attached forma heterocycle that is an aza-crown ether (e.g. 1-aza-12-crown-4,1-aza-15-crown-5, or 1-aza-18-crown-6).

A preferred group of compounds of formula (I) are compounds wherein: Ais an aryl or a heteroaryl ring; B″ is —NRa— wherein Ra is hydrogen,alkyl, or substituted alkyl; R¹ is hydrogen or alkyl; R² is selectedfrom a group consisting of formula (i), (ii), (iii), or “Het”:

wherein: —is an optional double bond; n, is an integer of from 1 to 4;n₂ is an integer of from 1 to 3; V is —CH—, —O—, —S(O)n₃— (where n₃ isan integer of from 0 to 2), or —NR⁴— (wherein R⁴ is hydrogen, alkyl,substituted alkyl, aryl, or heteroaryl); “Het” is a heteroaryl ringwhich optionally attaches the ligand to a linker; R³ is hydrogen, alkyl,amino, substituted amino, —OR^(a) (where R^(a) is hydrogen, alkyl, oracyl), or a covalent bond attaching the ligand to a linker; R⁵ ishydrogen, alkyl, amino, substituted amino, —OR^(b) (where R^(b) ishydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bondattaching the ligand to a linker; R⁶, R⁷, and R⁸ are, independently ofeach other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy,alkoxycarbonyl, alkyl optionally substituted with one, two or threesubstituents selected from halo, hydroxy, carboxy, alkoxycarbonyl,alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bondattaching the ligand to a linker; K is a bond or an alkylene group; K″is a bond, —C(O)—, —S(O)_(n4)— (where n₄ is an integer of from 0 to 2),or an alkylene group optionally substituted with a hydroxyl group; and Bis a heterocycloamino group which optionally attaches the ligand to alinker; provided that at least one of the R⁵, R⁶, R⁷, R⁸, “Het”, or theheterocycloamino group attaches the ligand to a linker.

A preferred compound of formula (I) is a compound of Formula (Ia):

wherein A, R¹, R², K, K″, B, X, R⁴⁶ and R⁴⁷ are as defined herein.

For a compound of Formula (Ia) a preferred group of compounds is thatwherein A is phenyl or pyridine; and K and K″ are bond.

For a compound of Formula (Ia) another preferred group of compounds isthat wherein A is phenyl or pyridine; R² is phenyl; and K and K″ arebond.

For a compound of Formula (Ia) another preferred group of compounds isthat wherein B has any of the preferred values identified herein.

The invention also provides a compound of formula (IV):

wherein L₂ is an organic group comprising at least one (e.g. 1, 2, 3, or4) primary, secondary, or tertiary amines. Typically, the amine of L₂should be basic, having a pH of at least about 5, and preferably atleast about 6, more preferably at least about 7. The nature of the groupL₂ is not critical provided the compound has suitable properties (e.g.solubility, stability, and toxicity) for its intended use (e.g. as adrug or as a pharmacological tool). Typically the group L₂ will have amolecular weight below 500 and preferably below about 300. Additionally,the group L₂ preferably comprises 5 or fewer hydrogen bond donors (e.g.OH, —NHR—, and —C(═O)NHR—) and ten or fewer hydrogen bond acceptors(e.g. —O—, —NRR—, and —S—). Preferably, the nitrogen of B shown informula (IV) is separated from an amine of the group L₂ by about 15angstroms to about 75 angstroms (based on conventionally acceptable bondlengths and angles). More preferably, the nitrogen of B is separatedfrom an amine of the group L₂ by about 25 angstroms to about 50angstroms. Preferred compounds of formula (IV) also have a log D betweenabout −3 and about 5. Using the above parameters, one skilled in the artcan readily determine compounds of formula (IV) possessing the desiredproperties for an intended use.

General Synthetic Schemes

Compounds of this invention can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Furthermore, it will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

These schemes are merely illustrative of some methods by which thecompounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to oneskilled in the art having referred to this disclosure.

Preparation of a Compound of Formula (I)

In general, compounds of Formula (I) can be prepared as illustrated anddescribed in Schemes A.

A compound of Formula (I) is prepared by covalently attaching oneequivalent of a compound of formula 1 with a compound of formula 2 whereX is a linker as defined herein, FG¹ is a functional group, FG² is afunctional group that is complimentary to FG¹, PG is a protecting group,and FG²PG is a protected functional group, to give an intermediate offormula (II). Deprotection of the functional group on the linker,followed by reaction of resulting compound 3 with one equivalent ofcompound 4, then provides a compound of Formula (I). The reactionconditions used to link compounds 1 and 4 to compound 2 and 3 depend onthe nature of the functional groups on compounds 1, 2, 3 and 4 which inturn depend on the type of linkage desired. Examples of the functionalgroups and the reaction conditions that can be used to generate aspecific linkage is described below.

TABLE I Representative Complementary Binding Chemistries First ReactiveGroup Second Reactive Group Linkage carboxyl amine amide sulfonyl halideamine sulfonamide hydroxyl alkyl/aryl halide ether hydroxyl isocyanateurethane amine epoxide β-hydroxyamine amine alkyl/aryl halide alkylaminehydroxyl carboxyl ester

Reaction between a carboxylic acid of either the linker or the ligandand a primary or secondary amine of the ligand or the linker in thepresence of suitable, well-known activating agents such asdicyclohexylcarbodiimide, results in formation of an amide bondcovalently linking the ligand to the linker; reaction between an aminegroup of either the linker or the ligand and a sulfonyl halide of theligand or the linker, in the presence of a base such as triethylamine,pyridine, and the like results in formation of a sulfonamide bondcovalently linking the ligand to the linker; and reaction between analcohol or phenol group of either the linker or the ligand and an alkylor aryl halide of the ligand or the linker in the presence of a basesuch as triethylamine, pyridine, and the like, results in formation ofan ether bond covalently linking the ligand to the linker.

Suitable dihydroxyl and dihalo starting materials useful forincorporating a group X into a compound of the invention are shown inthe following table. Preferably, an alcohol is reacted with a ligandbearing a leaving group to provide an ether bond, while a dihalocompound is preferably reacted with an amine of the ligand to form asubatituted amine.

No. X X1 

X2 

X3 

X4 

X5 

X6 

X7 

X8 

X9 

X10

X11

X12

X13

X14

X15

X16

X17

X18

X19

X20

X21

X22

X23

X24

X25

X26

X27

X28

X29

X30

X31

X32

X33

X34

X35

X36

X37

X38

X39

X40

X41

X42

X43

X44

X45

X46

X47

X48

X49

X50

X51

X52

X53

X54

X55 HOCH₂(CF₂)₈CH₂OH X56

X57

X58

X59

X60

X61

X62

X63

X64

X65

X66

X67

X68

X69 HOCH₂(CH₂)₄CH₂OH X70

X71

X72

X73

X74

X75

X76

X77

X78

X79

X80

X81

X82

X83

X84

X85

X86

X87

X88

X89

X90

X91

X92

X93

X94

X95

X96

X97

X98

X99

 X100 HOCH₂(CF₂)₃CH₂OH

Typically, a compound selected for use as a ligand will have at leastone functional group, such as an amino, hydroxyl, thiol or carboxylgroup and the like, which allows the compound to be readily coupled tothe linker. Compounds having such functionality are either known in theart or can be prepared by routine modification of known compounds usingconventional reagents and procedures.

A compound of formula (a) wherein A is phenyl, pyridyl, and the like canbe prepared as described in EP 747 355 and as described by Naito, R. etal., Chem. Pharm. Bull., 1998, 46(8), 1286.

Scheme B

L₁—H+R_(a)—X—L₂→(I)

A compound of formula (I) wherein L₁ comprises a nitrogen that is bondedto X, can be prepared by alkylating a corresponding compound of formulaL₁—H wherein —H is bound to the nitrogen, with a corresponding compoundof R_(a)—X—L₂ wherein X and L₂ have any of the values defined herein andR_(a) is a suitable leaving group. Suitable leaving groups an conditionsfor the alkylation of an amine are known in the art (for example, seeAdvanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed.,1992, Jerry March, John Wiley & Sons, New York. For example, R_(a) canbe halo (e.g. chloro, bromo, or iodo), methylsulfonyl, 4-tolylsulfonyl,mesyl, or trifluoromethylsulfonyl.

Accordingly, the invention provides a method for preparing a compound offormula (I) wherein L₁ comprises a nitrogen that is bonded to X,comprising alkylating a corresponding compound of formula L₁—H with acompound of R_(a)—X—L₂ wherein X and L₂ have any of the values definedherein and R_(a) is a suitable leaving group.

The invention also provides a compound of formula L₁—H wherein L₁, hasany of the values defined herein. The following compounds are preferredcompounds of formula L₁—H:

The invention also provides a compound of formula R_(a)—X—L₂ wherein X,and L₂ have any of the values defined herein and R_(a) is a suitableleaving group. The compound of formula L₁—H can also be alkylated bytreatment with an aldehyde of formula L₂—V—CHO (wherein —V—CH₂— isequivalent to —X—), under reductive alkylation conditions. Reagents andconditions suitable for carrying out the reductive alkylation of anamine are known in the art (for example, see Advanced Organic Chemistry,Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley& Sons, New York).

Accordingly, the invention provides a method for preparing a compound offormula (I) wherein L₁ comprises a nitrogen that is bonded to X,comprising alkylating a corresponding compound of formula L₁—H with acompound of formula L₂—V—CHO (wherein —V—CH₂— has any of the values for—X— described herein).

Scheme C

L₁—X—R_(a)+H—L₂→(I)

A compound of formula (I) wherein L₂ comprises a nitrogen that is bondedto X, can be prepared by alkylating a corresponding compound of formulaL₂—H wherein —H is bound to the nitrogen, with a corresponding compoundof L₁—X—R_(a) wherein X and L₁ have any of the values defined herein andR_(a) is a suitable leaving group. Suitable leaving groups an conditionsfor the alkylation of an amine are known in the art (for example, seeAdvanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed.,1992, Jerry March, John Wiley & Sons, New York. For example, R_(a) canbe halo (e.g. chloro, bromo, or iodo), methylsulfonyl, 4-tolylsulfonyl,mesyl, or trifluoromethylsulfonyl.

Accordingly, the invention provides a method for preparing a compound offormula (I) wherein L₂ comprises a nitrogen that is bonded to X,comprising alkylating a corresponding compound of formula L₂—H with acompound of L₁—X—R_(a) wherein X and L₁ have any of the values definedherein and R_(a) is a suitable leaving group.

The compound of formula L₂—H can also be alkylated by treatment with analdehyde of formula L₁—V—CHO (wherein —V—CH₂— is equivalent to —X—),under reductive alkylation conditions. Reagents and conditions suitablefor carrying out the reductive alkylation of an amine are known in theart (for example, see Advanced Organic Chemistry, Reaction Mechanismsand Structure, 4 ed., 1992, Jerry March, John Wiley & Sons, New York).

Accordingly, the invention provides a method for preparing a compound offormula (I) wherein L₂ comprises a nitrogen that is bonded to X,comprising alkylating a corresponding compound of formula L₂—H with acompound of formula L₁—V—CHO (wherein —V—CH₂— has any of the values for—X— described herein).

It will be understood that the alkylation reactions in Schemes B and Ccan optionally be carried out using suitably protected derivatives ofL₁—H, L₂—H, L₁—X—R_(a), R_(a)—X—L₂, L₁—V—CHO, and L₂—V—CHO. Suitableprotecting groups as well as conditions for their incorporation andremoval are known in the art (for example, see Greene, T. W.; Wutz, P.G. M. “Protecting Groups In Organic Synthesis” second edition, 1991, NewYork, John Wiley & sons, Inc.). Thus, a compound of formula (I) can alsobe prepared by deprotecting a corresponding compound of formula (I)bearing one or more protecting groups.

Accordingly, the invention provides a method for preparing a compound offormula (I) comprising deprotecting a corresponding compound of formula(I) that bears one or more protecting groups. The invention alsoprovides an intermediate compound of formula (I) that bears one or moreprotecting groups.

Combinatorial Synthesis

Compounds of formula (I) can conveniently be prepared usingcombinatorial synthesis methods (e.g. solid phase and solution phasecombinatorial synthesis methods) that are known in the art. For example,compounds of formula (I) can be prepared using combinatorial methodslike those escribed in International Patent Application PublicationNumber WO 99/64043.

Utility, Testing, and Administration Utility

The compounds of this invention are muscarinic receptor antagonists oragonists. A preferred sub-groug of compounds of the invention are M₂muscarinic receptor antagonists. Accordingly, the compounds andpharmaceutical compositions of this invention are useful in thetreatment and prevention of diseases mediated by these receptors such aschronic obstructive pulmonary disease, asthma, irritable bowel syndrome,urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, andAlzheimer's disease, senile dementia, glaucoma, schizophrenia,gastroesophogeal reflux disease, cardiac arrhythmia, hyper salvationsyndromes, and the like.

Testing

The ability of the compounds of formula (I) to inhibit a muscarinicreceptor (e.g. the M₂ or M₃ subtype) may be demonstrated using a varietyof in vitro assays and in vivo assays known in the field, or may bedemonstrated using an assay described in biological examples 1-6 below.

Pharmaceutical Formulations

When employed as pharmaceuticals, the compounds of this invention areusually administered in the form of pharmaceutical compositions. Thesecompounds can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular,intravesicular, and intranasal. These compounds are effective as bothinjectable and oral compositions. Such compositions are prepared in amanner well known in the pharmaceutical art and comprise at least oneactive compound.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds described hereinassociated with pharmaceutically acceptable carriers. In making thecompositions of this invention, the active ingredient is usually mixedwith an excipient, diluted by an excipient or enclosed within such acarrier which can be in the form of a capsule, sachet, paper or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.001 to about 1 g, usually about 0.1 toabout 500 mg, more usually about 1 to about 50 mg, of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient. Preferably, the compound ofFormula (I) above is employed at no more than about 20 weight percent ofthe pharmaceutical composition, more preferably no more than about 15weight percent, with the balance being pharmaceutically inertcarrier(s).

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as corn oil,cottonseed oil, sesame oil, coconut oil, or peanut oil, as well aselixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

In the examples below, the following abbreviations have the followingmeanings. Unless otherwise stated, all temperatures are in degreesCelsius. If an abbreviation is not defined, it has its generallyaccepted meaning.

g gram mg milligram min minute ml milliliter mmol millimol

Synthetic Examples Example 1

The intermediate compound of formula 1B was prepared as follows.

Biphenyl-2-isocynate (50 g, 256 mmol) was dissolved in 400 mL anhydrousacetonitrile in a 2L rbf at room temperature. After cooling to 0 C.using an ice bath, a solution of 4-amino-N-benzylpiperidine (48.8 g, 256mmol) dissolved in 400 mL anhydrous acetonitrile was added over 5minutes. Precipitate was observed immediately. After 15 minutes, anadditional 600 mL anhydrous acetonitrile was added to permit stirring ofthe viscous solution for 12 h at 35° C. The solids were filtered, andwashed with cold acetonitrile then dried under vacuum, yielding acolorless solid (100 g, 98%). This material was characterized by ¹H-NMR,¹³C-NMR and MS.

Compound 1A (20 g, 52 mmol) was dissolved in 800 mL of a 3:1 mixture ofanhydrous methanol to anhydrous DMF. Aqueous HCl was added (0.75 mL of37% conc solution, 7.6 mmol) and nitrogen gas bubbled through thesolution vigorously for 20 min. Pd(OH)2 (Pearlman's catalyst, 5 g) wasadded under a stream of nitrogen. A large balloon containing H2 gas wasplaced and the solution allowed to stir for 4d. The solution was passedtwice through pads of celite to remove the catalyst, and the solutionevaporated to dryness under vacuum to yield a colorless solid (13 g,85%). This material was characterized by ¹H-NMR, ¹³C-NMR and MS.

Following the procedures described above but substituting theappropriate starting materials, the compounds of the invention (formula(VI)) listed in Table A below were prepared. Unless otherwise noted, forthe compounds in Tables A—F, L₂ is attached to X through the secondarynon-aromatic amine of L₂.

TABLE A (VI)

Compound L2 Mass Spec Found  1 A224 411.6  2  A87 488.6  3 A172 517.7  4 A90 514.7  5 A141 607.8  6 A169 517.7  7 A164 517.78  8 A208 451.6  9A199 467.6 10  A23 534.6 11  A70 542.7 12  A73 542.7 13 A156 605.8 14 A95 511.7 15 A115 467.6 16 A156 605.8 17 A516 487.7 18 A364 511.7 19 A96 485.6 20 A508 537.7 21 A509 537.7 22 A190 505.7 23 (135) 616.8 24 A51 532.7 25 A524 496.7 26 A410 542.7 27 A368 516.7 28  A84 515.7 29 A65 516.7 30 A193 548.8 31 A142 604.8 32 A177 556.8 33  A68 515.7 34A501 529.7 35 A525 574.7 36 A168 554.7 37 A437 604.8 38  A61 536.7 39A117 480.6 40 A166 542.7 41   78 520.7 42  A49 583.7 43 A367 514.7 44A526 572.7 45 A229 547.7 46 A239 427.6 47 A179 483.7 48 A182 437.6 49 A55 467.6 50 A510 514.7 51 A502 502.7 52  A43 551.7 53 A218 518.7 54A123 494.6 55 A126 538.7 56 A134 534.6 57 A120 480.6 58 A157 517.7 59A396 533.7 60  A25 569.7 61  A83 559.7 62 A161 469.6 63  A11* 571.1 64A420 554.7 65 A135 541.7 66 A411 543.7 67  A88 531.7 68 A386 527.7 69A404 538.7 70  A72 529.7 71  A26 569.8 72  A75 513.7 73 A419 553.7 74A375 517.7 75  A20 527.7 76 A427 571.7 77 A527 619.8 78  A9 485.6 79A520 467.6 80  A19 453.6 81 A513 551.7 82  A10 517.7 83 A110 466.6 84 A4 494.6 85  A19 453.6 86 A103 530.7 87  A60 536.7 88 A131 600.7 89A114 440.6 90 A197 468.6 91 A151 451.6 92 A195 463.6 93 A528 495.7 94A347 487.7 95 A328 467.6 96  A22 526.7 97 A336 480.6 98  A77 585.8 99A145 452.6 100  A211 550.7

Following the procedures described above but substituting appropriatestarting materials, the compounds of the invention (formula (VII))listed in Table B below were prepared.

TABLE B (VII)

(VII) Compound L2 Mass Spec Found 101 A224 395.6 102  A87 472.6 103 A529381.5 104 A530 533.1 105 A172 501.7 106 A141 591.8 107 A164 501.7 108A199 451.6 109  A70 526.7 110  A73 526.7 111 A156 589.8 112 A230 521.7113 A391 515.7 114  A95 495.7 115 A156 589.8 116 A516 471.7 117  A97495.7 118  A96 469.6 119 A508 521.7 120 A509 521.7 121 A190 489.7 122A435 600.8 123 A410 526.7 124  A84 499.7 125 A193 532.8 126 A142 588.8127 A177 540.8 128  A68 499.7 129 A433 588.8 130 A166 526.7 131  A31498.7 132 A526 556.7 133 A436 616.1 134  A50 602.1 135 A132 505.7 136A231 526.5 137 A229 531.7 138 A401 522.1 139 A373 501.7 140  A90 498.7141 A502 486.7 142  A43 535.7 143  A43^(@) 536.7 144 A576 522.7 145 A374501.7 146  A17 511.7 147  A21 517.7 148  A83 543.7 149 A531 538.7 150A125 525.7 151 A210 527.7 152  A88 515.7 153  A78 511.7 154 A404 522.7155  A72 513.7 156  A26 553.8 157  A75 497.7 158 A419 537.7 159 A527603.8 160 A520 451.6 161 A513 535.7 162 A164 501.7 163  A4 478.7 164A521 515.7 165  A60 520.7 166 A522 584.7 167 A192 551.7 168 A122 533.7169 A109 499.7 170 A383 507.7 171 A395 516.7 172 A503 594.8 173 A528479.7 174  A99 471.7 175  A22 510.7 176 A532 569.8

Following the procedures described above but substituting appropriatestarting materials, the compounds of the invention (formula (VIII))listed in Table C below were prepared.

TABLE C (VIII)

Compound L2 Mass Spec Found 177 A508 607.8 178 A509 607.8 179 A501 599.8180 A90 584.8 181 A502 572.8 182 A43 621.8 183 A513 621.8 184 A503 681.0185 A87 558.8 186 A164 587.8 187 A90 584.8 188 A90^(@) 585.8 189 A10587.8 190 A172 587.8 191 A208 521.7 192 A330 537.8 193 A70 612.9 194 A73612.9 195 A8 601.8 196 A95 581.8 197 A115 537.8 198 A516 557.8 199 A97581.8 200 A96 555.8 201 A358 575.9 202 A517 687.0 203 A62 612.9 204 A74586.8 205 A84 585.8 206 A65 586.8 207 A193 618.9 208 A142 674.9 209 A177626.9 210 A501 585.8 211 A217 644.8 212 A168 624.9 213 A166 612.9 214A31 584.8 215 A28 642.9 216 A104 702.3 217 A144 608.2 218 A373 587.8 219A90^(@) 585.8 220 A43^(@) 622.8 221 A576 608.8 222 A374 587.8 223 A17597.9 224 A396 603.8 225 A214 625.9 226 A83 629.8 227 A418 622.9 228A135 611.6 229 A210 613.9 230 A88 601.8 231 A404 608.8 232 A121 624.8233 A520 537.8 234 A164 587.8 235 A4 564.8 236 A521 601.8 237 A60 606.9238 A522 670.9 239 A109 585.8 240 A22 596.8 241 A532 655.9 242 A397604.7 243 A120 550.8 244 A533 509.7 245 A505* 626.9 246 A506 598.8 247A431 659.9 248 A388 597.9 249 A366 583.8 250 A534 578.8 251 A417 622.9252 A577 575.8 253 A319 536.7 254 A381 593.8 255 A338 550.8 256 A329537.8 257 A403 608.8 258 A333 549.8

Following the procedures described above but substituting appropriatestarting materials, the compounds of the invention (formula (IX)) listedin Table D below were prepared.

TABLE D (IX)

Compound L2 Mass Spec Found 259 A508 591.8 260 A509 591.8 261 A501 583.8262 A510 568.8 263 A502 556.8 264 A43 605.8 265 A512 581.8 266 A513605.8 267 A503 665.0 268 A223 542.8 269 A224 465.7 272 A535 661.9 273A536 571.8 274 A537 571.8 275 A306 505.7 276 A580 521.8 277 A578 588.7278 A538 596.9 279 A539 596.9 280 A321 520.8 281 A156 659.9 282 A400591.9 283 A8 585.8 284 A363 565.8 285 A359 560.8 286 A324 521.8 287 A156659.9 288 A516 541.8 289 A364 565.8 290 A346 539.8 291 A581 559.9 292A517 671.0 293 A394 586.8 294 A410 596.9 295 A368 570.8 296 A84 569.8297 A369 570.8 298 A193 602.9 299 A432 658.9 300 A423 610.9 301 A68569.8 302 A525 628.8 303 A168 608.9 304 A45 658.9 305 A398 590.8 306A117 534.8 307 A166 596.9 308 A378 574.9 309 A198 523.8 310 A137 534.8311 A316 520.7 312 A339 534.8 313 A322 520.8 314 A352 548.8 315 A430637.9 316 A384 568.8 317 A28 626.9 318 A436 686.3 319 A50 672.2 320 A132575.8 321 A205 550.8 322 A154 566.8 323 A413 601.8 324 A144 592.2 325A301 481.7 326 A344 537.8 327 A182 491.7 328 A373 571.18 329 A340 535.8330 A325 521.8 331 A94 567.8 332 A218 572.8 333 A348 548.8 334 A519588.9 335 A126 592.8 336 A397 588.7 337 A155 571.18 338 A308 507.7 339A387 581.9 340 A311 521.8 341 A21 587.8 342 A426 623.9 343 A422 609.9344 A424 613.8 345 A418 606.9 346 A161 523.7 347 A11 625.9 348 A420608.8 349 A406 595.8 350 A210 597.9 351 A374 585.8 352 A386 581.9 353A540 592.8 354 A72 583.8 355 A26 623.9 356 A365 567.8 357 A419 607.9 358A341 535.8 359 A412 599.8 360 A121 608.8 361 A375 571.8 362 A385 581.8363 A427 625.9 364 A527 674.0 365 A345 539.8 366 A327 521.8 367 A583507.7 368 A227 673.0 369 A312 511.7 370 A4115 603.8 371 A376 571.8 372A98 592.8 373 A317 520.7 374 A4 548.8 375 A165 535.7 376 A380 577.8 377A541 585.8 378 A584 589.8 379 A311 507.7 380 A521 585.8 381 A390 584.9382 A399 590.9 383 A131 654.9 384 A27 495.7 385 A204 548.8 386 A122603.9 387 A350 548.8 388 A425 617.9 389 A109 569.8 390 A542 664.0 391A114 494.7 392 A331 522.7 393 A235 577.8 394 A543 586.8 395 A151 505.8396 A313 517.7 397 A528 549.9 398 A99 541.8 399 A328 521.8 400 A384580.8 401 A314 519.8 402 A335 534.8 403 A360 562.2 404 A77 639.9 405A145 506.7 406 A71 563.8 407 A124 523.7 408 A377 573.8 409 A416 604.8410 A329 521.8 411 A43 606.8 412 A307 505.8 413 A397 588.7 414 A337#534.8 415 A303 493.7 416 A544 610.9 417 A506 582.8 418 A431 643.9 419A388 581.9 420 A366 567.8 421 A523 562.8 422 A545 606.9 423 A577 559.8424 A319 520.7 425 A381 577.8 426 A351 548.8 427 A338 534.8 428 A362563.8 429 A507 477.7 430 A402 592.8 431 A403 592.8 432 A315 519.8 433A333 533.8

Following the procedures described above but substituting appropriatestarting materials, the compounds of the invention (formula (X)) listedin Table E below were prepared.

TABLE E (X)

Compound L2 Mass Spec Found 434 A130 525.7 435 A105 521.8 436 A356 571.8437 A415 617.8 438 A579 585.8 439 A98 606.8 440 A317 534.8 441 A349562.8 442 A465 549.8 443 A380 591.8 444 A546 599.8 445 A547 548.8 446A548 587.8 447 A386 676.9 448 A311 521.8 449 A521 599.9 450 A127 490.7451 A390 598.9 452 A399 604.9 453 A342 550.8 454 A27 509.7 455 A549562.9 456 A550 635.9 457 A238 617.9 458 A350 562.8 459 A425 631.9 460A109 583.9 461 A114 508.7 462 A331 536.8 463 A551 585.8 464 A235 591.9465 A395 600.8 466 A13 615.8 467 A552 507.8 468 A151 519.8 469 A313531.8 470 A35 507.8 471 A99 555.8 472 A328 535.8 473 A22 594.9 474 A314533.8 475 A336 548.8 476 A228 684.0 477 A360 576.2 478 A145 520.7 479A302 505.8 480 A71 577.8 481 A553 656.9 482 A124 537.8 483 A554 587.8484 A416 618.9 485 A555 625.9 486 A556 701.0 487 A557 716.0 488 A558638.9 489 A559 624.8 490 A560 654.0 491 A561 654.0 492 A508 605.8 493A509 605.8 494 A501 597.9 495 A510 582.8 496 A502 570.8 497 A43 619.9498 A512 595.8 499 A513 619.9 500 A503 679.0 501 A504 556.8 502 A514613.9 503 A402 606.9 504 A403 606.9 505 A397 602.8 506 A337 548.8 507A303 507.7 508 A505 624.9 509 A506 596.9 510 A431 658.0 511 A388 595.9512 A366 581.9 513 A523 576.8 514 A417 620.9 515 A577 573.8 516 A319534.8 517 A381 591.8 518 A351 562.8 519 A338 548.8 520 A362 577.8 521A507 491.7 522 A324 535.8 523 A315 533.8 524 A333 547.8 525 A427 718.8526 A402 685.8 527 A562 506.7 528 A563 506.7 529 A564 520.8 530 A565731.0 531 A370 585.8 532 A371 585.8 533 A372 585.8 534 A587 519.7 535A330 535.8 536 A320 534.8 537 A578 602.8 538 A588 548.8 539 A538 610.9540 A539 610.9 541 A321 534.8 542 A156 674.0 543 A141 675.9 544 A569687.0 545 A400 605.9 546 A391 599.9 547 A363 579.8 548 A359 574.9 549A311 535.8 550 A570 602.9 551 A515 674.0 552 A178 680.0 553 A364 579.8554 A346 553.8 555 A358 573.9 556 A517 685.0 557 A571 634.0 558 A51600.8 559 A64 564.8 560 A67 619.9 561 A62 610.9 562 A180 617.9 563 A74584.8 564 A84 583.8 565 A65 584.8 566 A193 616.9 567 A432 672.9 568 A200591.9 569 A177 624.9 570 A572 632.0 571 A174 603.9 572 A68 583.8 573A525 642.9 574 A168 622.9 575 A45 673.0 576 A61 604.8 577 A117 548.8 578A166 610.9 579 A378 588.9 580 A137 548.8 581 A34 534.8 582 A93 548.8 583A59 562.9 584 A585 651.9 585 A31 582.8 586 A28 640.9 587 A436 700.3 588A50 686.3 589 A3 675.0 590 A379 589.8 591 A573 610.7 592 A355 564.8 593A413 615.9 594 A401 606.3 595 A301 495.7 596 A179 551.8 597 A82 551.8598 A12 585.8 599 A55 535.8 600 A133 607.9 601 A94 581.8 602 A100 570.8603 A123 562.8 604 A589 606.9 605 A134 602.8 606 A203 548.8 607 A17595.9 608 A66 535.8 609 A214 623.9 610 A574 627.9 611 A154 585.8 612 A6636.9 613 A185 521.8 614 A2 525.7 615 A119 569.8 616 A21 601.8 617 A25637.9 618 A33 620.9 619 A161 537.8 620 A11* 639.9 621 A420 622.9 622A135 609.9 623 A210 611.9 624 A88 599.9 625 A72 597.9 626 A69 521.8 627A26 637.9 628 A365 581.9 629 A171 621.9 630 A81 549.8 631 A412 613.9 632A121 622.9 633 A18 663.9 634 A232 585.8 635 A575 670.0 636 A20 595.8 637A153 639.9 638 A590 688.0 639 A91 477.7 640 A9 553.8 641 A194 535.8 642A310 521.8 643 A227 687.0

Following the procedures described above but substituting appropriatestarting materials, the compounds of the invention (formula (XI)) listedin Table F below were prepared.

TABLE F (XI)

Compound L2 Mass Spec Found 270 A224 609.6 271 A87 686.7

In the above tables *signifies that L₂ is attached to X through thepiperidine nitrogen of L₂; @signifies that L₂ is attached to X throughthe pyridine nitrogen of L₂; and #signifies that L₂ is attached to Xthrough the pyrrolidine nitrogen of L₂.

Formulation Examples Example 1

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

Example 2

A tablet Formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

Example 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

Example 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10%solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesiumstearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Example 5

Capsules, each containing 40 mg of medicament are made as follows:

Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch 109.0mg Magnesium stearate 1.0 mg Total 150.0 mg

The active ingredient, starch, and magnesium stearate are blended,passed through a No. 20 mesh U.S. sieve, and filled into hard gelatincapsules in 150 mg quantities.

Example 6

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient 25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Example 7

Suspensions, each containing 50 mg of medicament per 5.0 mL dose aremade as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mgSucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

Example 8

A formulation may be prepared as follows:

Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch 407.0mg Magnesium stearate 3.0 mg Total 425.0 mg

The active ingredient, starch, and magnesium stearate are blended,passed through a No. 20 mesh U.S. sieve, and filled into hard gelatincapsules in 425.0 mg quantities.

Example 9

A formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference in its entirety. Such patches may be constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.

Other suitable formulations for use in the present invention can befound in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 18th ed., 1990).

Biological Examples Example 1 M₂ Muscarinic Receptor In Vitro BindingAssay

The M₂ muscarininc receptor binding activity of compounds of theinvention was tested as follows.

SF9 cell membranes containing human M₂ muscarinic receptor was obtainedfrom NEN (Boston, Mass.). In 96-well microtiter plates, eight serialfive-fold dilutions were prepared with the compound to be assayed; thehighest concentration was typically 4 μM (4× the final concentration).To 100 μl of compound dilution was added 150 μL M₃ receptor membranepreparation in PBS/1.0 mM MgCl₂/pH 7.4. 50 μl of 3.2 nM3H-N-methylscopolamine radioligand was added. The total volume in eachwell was then 300 μl. The filter plate was pre-blocked using 0.3% PEIfor at least 15 minutes, and then washed twice with 200 μl PBS. Theassay plate was incubated for 1 hour at room temperature with gentleshaking. The contents of the assay plate were then transferred to thefilter plate, and washed three times using 200 μl PBS. About 40 μl ofscint was added to each well and then the plate was allowed to sit atroom temperature for 2 h, and then counted using a Packard Topcount NXT.Counting was typically performed for 1 minute per well using a standardprotocol on a Packard top counter. The raw data was fit to a standard4-parameter equation given below and a value of IC₅₀ obtained.

Y=(a−d)/(1+(x/c)^(b))+d where

Y = cpm a = total binding b = slope c = IC₅₀ x = [compound] d =nonspecific binding

Representative compounds of the invention were found to have pK_(b)values of greater than 6, and to have IC₅₀ values of less than about 50μm.

A similar protocol was used to measure M1, M3, M4 and M5 humanmuscarinic receptor activity.

Example 2

Rat Heart Muscarinic Receptor in vitro Binding Assay

Tissue (rat heart) muscarininc receptor binding activity of compounds ofthe invention was tested as follows.

Muscarinic receptor enriched membranes were isolated from whole hearts(Pelfreeze Laboratories). Rat heart tissue was typically prepared asfollows. 25 μl of ice cold buffer (20 mM HEPES, 100 mM NaCl/10 mM MgCl₂at pH 7.5 with “Complete” protease inhibitor cocktail purchased fromBoehringer Mannheim was added into an oakridge tube. To the tube wasthen added 2 g of rat heart (purchased from Harlan). The contents of thetube were then transferred to a wheaton glass cylinder and homogenizedusing a Polytron homogenizer (setting 22, 15 seconds×2), and thentransferred back to the oakridge tube, and centrifuged for 10 minutes at1500 g. The supernatant was removed and then centrifuged for 20 minutesat 45000 g. The supernatant was removed and the pellet resuspended in 5mL buffer and transferred to a wheaton glass cylinder. This material wasthen homogenized using a Potter type glass teflon homogenizer with 7-8passes. The material was then transferred to an oakridge tube and thetotal volume was brought up to 25 mL. This material was then centrifugedfor 20 minutes at 45000 g, and the pellet re-suspended in 2 mL bufferusing 2 passes of a teflon homogenizer, and stored at −80° C. untilused.

A protocol similar to that used for cloned receptor binding was used:Eight serial five-fold dilutions were prepared with the compound to beassayed; the highest concentration was typically 4 μM (4× the finalconcentration). To 50 μl of compound dilution in a 96-well assay platewas added an appropriate amount of rat heart membrane (usually 12.5 μlof membrane prep in 87.5 μl of 20 mM HEPES, 100 mM NaCl/10 mM MgCl₂ atpH 7.5). The amount of membrane added depends in general on the resultsof signal optimization, and ranges from 6.25-12.5 μl. Last, 50 μl of2.12 nM 3H-N-methylscopolamine radioligand was added. The total volumein each well was 200 μl. The filter plate was pre-blocked using 0.3% PEIfor at least 15 min., and then washed twice with 200 μl PBS. The assayplate was incubated for 1 h at room temperature with gentle shaking. Thecontents of the assay plate were then transferred to the filter plate,and washed three times using 200 μl PBS. About 40 μl of scint was addedto each well and then the plate was allowed to sit at room temperaturefor 18 h, and then counted using a Packard Topcount NXT. Counting wastypically performed for 1 min., per well using a standard protocol onthe Packard counter. The data was fit to normal isotherms and values forinhibition constants were extracted. Representative compounds of theinvention were found to have pK_(b) values of greater than 6, and tohave IC₅₀ values of less than about 50 μm.

A similar procedure was used to measure muscarinic receptor binding atrat submaxillary gland, rat bladder, rat submandibular gland, guinea pigheart, guinea pig submaxillary gland, guinea pig bladder, and guinea pigsubmandibular gland, as well as in similar human tissues.

Example 3 Rat Bladder M₃ in vitro Binding Assay

Bladder was comprised of both M₂ and M₃ muscarinic receptors. The ratiowas typically 4:1 M₂:M₃. In order to measure binding of test compoundsto one of M₂ or M₃, the other was blocked with a reversible ligand thatbinds selectively to that receptor. The following example illustratesthe procedure for M₃ bladder binding.

Membranes from rat bladder were prepared in a similar fashion to thatused to isolate heart membrane above. Eight serial five-fold dilutionswere prepared with the compound to be assayed in compound dilutionbuffer (20 mM HEPES/100 mM NaCl/10 mM MgCl₂/4 μM Methoctramine); thehighest concentration was typically 4 μM (4× the final concentration).The concentration of methoctramine was sufficient to block >99% of theM₂ receptor in bladder, but less than 40% of the M₃ receptor in bladder.To 50 μl of compound dilution in a 96-well assay plate was added anappropriate amount of rat heart membrane (usually 25 μl of membrane prepin 75 μl of 20 mM HEPES, 100 mM NaCl/10 mM MgCl₂ at pH 7.5). The amountof membrane added depended in general on the results of signaloptimization, and ranged from 12.5-25. Last, 50 μl of 2.12 nM3H-N-methylscopolamine radioligand in compound dilution buffer wasadded. The total volume in each well was 200 μl. The final concentrationof methoctramine was 2 μM. The filter plate was pre-blocked using 0.3%PEI for at least 15 mins., and then washed twice with 200 μl PBS. Theassay plate was incubated for 1 hour at room temperature with gentleshaking. The contents of the assay plate was then transferred to thefilter plate, and washed three times using 200 μl PBS. About 40 μl ofscint was added to each well, the plate was allowed to sit at roomtemperature for 18h, and then counted using a Packard Topcount NXT.Counting was typically performed for 1 minute per well using a standardprotocol on the Packard counter. The data was fit to normal isothermsand values for inhibition constants were extracted. Representativecompounds of the invention were found to have IC₅₀ values of less thanabout 500 μm.

A similar procedure was used to measure binding at bladder M₂, but inthis case, 2 μM Darifenacin was used to block >99% of the M₂ receptor,but minimal M₃ receptor.

Example 4 Ex Vivo Rat Bladder Contraction Assay

The ability of the test compound to inhibit cholinergically stimulatedbladder contraction was tested as follows.

Male Sprague-Dawley rats weighing 250-300 g are killed by CO₂ overdose.The bladder was removed and placed in a petri dish containingKrebs-Henseleit solution at room temperature. The apex and dome areas ofthe bladder were discarded and the remaining tissue cut intolongitudinal strips (4 from each rat). The strips were mounted in anorgan bath containing Krebs-Henseleit solution at 37° C., under aresting tension of 0.5 g. The tissues were allowed to equilibrate for 60min., (washes at 0, 30 and 60 min.). Tension was readjusted to 1 g asnecessary. A cumulative concentration response curve to carbachol (10-8M to 10-5 M (e.g.) in 3-fold increments) was constructed in each tissue.Tissues were then washed every 5 min., for 30 min., and tensionreadjusted to 1 g. After additional 30 min., muscarinic antagonist(typically 1×10-7 M) or vehicle was added. Thirty minutes afterantagonist or vehicle addition, a cumulative concentration responsecurve to carbachol (10-8M to 10-3M (e.g.)) was constructed. Data fromeach concentration response curve was expressed as a percentage of themaximum contraction to carbachol. The EC₅₀ values were calculated. Theconcentration-ratios were calculated taking into account any spontaneousshift in the control tissue. For competitive antagonists, the pKb valuewas calculated using the following equation:${pKB} = {- \frac{\log \left\lbrack {{antagonist}\quad {concentration}} \right\rbrack}{{CR} - 1}}$

Representative compounds of the invention were found to have pK_(b)values of greater than 5.

Example 5 In vivo Rat Salivation Assay

Male Sprague-Dawley rats weighing 250-300 g were anesthetized withpentobarbital (60 mg/kg i.p.). Rats were placed on a heated blanketunder a 20 degree incline. A swab was placed in the rat's mouth.Muscarinic antagonist or vehicle was administered i.v. via the tailvein. After 5 min., oxotremorine (0.3 mg/kg) was administered s.c. Theswab was discarded and replaced by a pre-weighed swab. Saliva was thencollected for 15 min. After 15 min., the swab was weighed and thedifference in its weight was used to calculate the antisecretory potencyof the antagonists. The data was fit to normal isotherms and ID₅₀ valueswere extracted.

Example 6 In vivo Bladder Assay

Male Sprague-Dawley rats weighing 250-300 g were anesthetized withurethane (1.3 g/kg, i.p.), inactin (25 mg/kg, i.p.), and xylazine (4 mg,i.p.). The jugular (or femoral) vein was isolated and ligated and asmall incision was made in the vein distal to the ligation. A catheter(micro-Renathane tubing (0.014 mm ID×0.033 mm OD) filled with saline wasinserted into the vein and secured into place with suture thread. Thetrachea was isolated and placed in a small hole between two of therings. Tubing (1.57 mm ID×2.08 mm OD) was inserted into the trachea andtied into place with suture thread. The incision was closed leaving thetubing exposed. The tracheotomy was to prevent the animal fromasphyxiating on his own saliva following oxotremorine administration.The stomach was shaved and then cleaned with ethanol. A midline sagitalincision was made in the skin and muscle layers of the lower stomach.The bladder was exposed and the saline filled cannula (22-gauge needleattached to a pressure transducer with PE 90 tubing) was inserted intothe apex of the bladder to the most distal part of the bladder. Thebladder was placed back into the peritoneal cavity. The bladder wasemptied manually by disconnecting the cannula and allowing the contentsto flow out until the bladder was approximately 1 cm in diameter. Theincision was closed with suture thread, first the muscle layer, then theskin in order to keep the bladder moist and warm. The exposed portion ofthe cannula to the skin surface was sutured to hold it in place. After15 min. oxotremorine (0.3 mg/kg, SC, baseweight) was injected. After 10min., (or until baseline stabilized) a test compound or a referencestandard was injected with a dose equivalent to 0.005-0.01 mg/kg, IV,baseweight of atropine that produced a 30-70% decrease in intraluminalpressure. After 5 min., a high dose of atropine 0.1 mg/kg was injected,i.v., to establish the true 100% inhibition point.

For data analysis, the oxotremorine response (zero inhibition) wasdetermined by measuring the mean pressure 1 minute prior to theantagonist injection. Then, to assess antagonist inhibition, meanpressure was mesured beginning at 1 minute and ending 2 minutes afterantagonist administration. If the pressure had not leveled off after 1minute, a wait was initiated until it was stable and then a 1-minutesample of the mean was taken. Lastly, to determine the true 100%inhibition point, the mean pressure was measured beginning 1 minutes andending 2 minutes after the high dose atropine challenge. The percentinhibition by the antagonist can be determined by the ratio of thedecrease from the zero to 100% values.

The formula is: oxotremorine mean−treatment mean *100

oxotremorine mean−atropine mean.

Additionally, the activity of a compound of the invention on othertissues can be determined using screening protocols that are known inthe art. For example, an assessment of increased locomotor activity(assay for CNS penetration) can be carried out as described by Sipos ML, et al., (1999) Psychopharmacology 147(3):250-256; an assessment ofthe effects of a compound on gastrointestinal motility can be carriedout as described by Macht D I, and Barba-Gose J (1931) J Am Pharm Assoc20:558-564; an assessment of the effects of a compound on pupil diameter(mydriasis) can be carried out as described by Parry M, Heathcote B V(1982) Life Sci 31:1465-1471; and an assessment of a compounds effectson urinary bladder in dog can be carried out as described by Newgreen DT, et al. (1996) J Urol 155:600A.

Preferred compounds of the invention may display selectivity for one ormore tissues over other tissues. For example, compounds of the inventionthat are useful for treating urinary incontinence may show higheractivity in the assay of Example 6 than in the assay of Example 5.

Preferred compounds useful for treating urinary incontinence andirritable bowel syndrome have greater antagonist activity at the M₂receptor than at the M₃ receptor or the other muscarinic receptors.

Preferred compounds useful for treating unwanted salivation have greaterantagonist activity at the M₃ receptor than at the M₂ receptor or theother muscarinic receptors.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

What is claimed is:
 1. A compound of formula (IVa):

wherein: X is a group of formula: —X^(a)—Z—(Y^(a)—Z)_(m)—Y^(b)—Z—X^(a)—; m is an integer of from 0 to 20; X^(a) at each separate occurrence isselected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—,—C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— or a covalent bond; Z at eachseparate occurrence is selected from the group consisting of alkylene,substituted alkylene, cycloalkylene, substituted cylcoalkylene,alkenylene, substituted alkenylene, alkynylene, substituted alkynylene,cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene,heterocyclene, or a covalent bond; Y^(a) and Y^(b) at each separateoccurrence are selected from the group consisting of —O—, —C(O)—,—OC(O)—, —C(O)O—, —NR—, —S(O)n-, —C(O)NR′—, —NR′ C(O)—, —NR′ C(O)NR′—,—NR′ C(S)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —OC(O)—NR′—, —NR′—C(O)—O—,—N═C(X^(a))—NR′—, —NR′—C(X^(a))═N—, —P(O)(OR′)—O—, —O—P(O)(OR′)—,—S(O)_(n)CR′ R″—, —S(O)_(n)—NR′—, —NR′—S(O)_(n)—, —S—S—, and a covalentbond; n is 0, 1 or 2; R, R′ and R″ at each separate occurrence areselected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl,aryl, heteroaryl and heterocyclic; L₂ is a group of formula (d) or (e):

R⁴⁶ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, orheterocycle; R⁴⁷ is alkyl, substituted alkyl, aryl, acyl, heterocycle,or —COOR⁵⁰ where R⁵⁰ is alkyl; or R⁴⁶ and R⁴⁷ together with the nitrogenatom to which they are attached form heterocycle, which heterocycle canalso optionally be substituted with one or more alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;R⁴⁸ is a covalent bond that attaches L₂ to X and R⁴⁹ is alkyl; providedat least one of X^(a), Y^(a), Y^(b) or Z is not a covalent bond; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein L₂ is a group of the formula (d) and R⁴⁶ is alkyl or substitutedalkyl; R⁴⁷ is alkyl, substituted alkyl, or heterocycle; or R⁴⁶ and R⁴⁷together with the nitrogen atom to which they are attached formheterocycle.
 3. The compound of claim 1 wherein L₂ is a group of formula(d) wherein R⁴⁶ and R⁴⁷ together with the nitrogen atom to which theyare attached form heterocycle which is substituted with 1 to 5substituents independently selected from the, group consisting ofsubstituted alkyl, alkenyl, substituted alkenyl, alkynyl, andsubstituted alkynyl.
 4. The compound of claim 1 wherein L₂ is a group ofthe formula (d) and R⁴⁶ and R⁴⁷ together with the nitrogen atom to whichthey are attached form a piperidine or pyrrolidine ring which ring isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl,thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy,substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino,alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, and substituted alkynyl.
 5. The compound of claim 1 wherein L₂has any one of the formula A1-A590 shown hereinabove.
 6. The compound ofclaim 1 wherein L₂ is A234, A363, A364, A153, A28, A324, A329, A562,A87, or A239.
 7. The compound of claim 1, wherein X is alkyleneoptionally substituted with one, two, or three hydroxy groups, alkylenewherein one, two or three carbon atoms have been replaced by an oxygenatom, or -alkylene-phenylene-alkylene- wherein the phenylene ring isoptionally substituted with one or two chloro or fluoro groups.
 8. Thecompound of claim 1 wherein X is an alkylene group having from 3 to 20carbon atoms; wherein one or more carbon atoms in the alkylene group isoptionally replaced with —O—; and wherein the chain is optionallysubstituted on carbon with one or more hydroxyl.
 9. The compound ofclaim 1 wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl,2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.
 10. The compound ofclaim 1 wherein X has the formula:

wherein the phenyl ring is optionally substituted with 1, 2, or 3 fluorogroups.
 11. The compound of claim 1 wherein X has one of the followingformula:


12. Compound number 1-643 as described in Table A, Table B, Table C,Table D, Table E, or Table F; or a pharmaceutically acceptable saltthereof.
 13. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim 11.